Choroidal neovascularization can lead to hemorrhage and fibrosis, with resulting visual loss in a number of conditions of the eye, including, for example, age-related macular degeneration (“AMD”), ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, and certain inflammatory diseases. One of the disorders, namely, AMD, is the leading cause of severe vision loss in people aged 65 and above (Bressler et al. (1988) Surv. Ophthalmol. 32: 375-413; Guyer et al. (1986) Arch. Ophthalmol. 104: 702-705; Hyman et al. (1983) Am. J. Epidemiol. 188: 816-824; Klein & Klein (1982) Arch. Ophthalmol. 100: 571-573; Leibowitz et al. (1980) Surv. Ophthalmol. 24: 335-610). Age-related macular degeneration is the leading cause of legal blindness in individuals older than 50 years in the Western societies (Bressler et al. (1988) supra). Although clinicopathologic descriptions have been made, little is understood about the etiology and pathogenesis of the disease.
Dry AMD is the more common form of the disease, characterized by drusen, pigmentary and atrophic changes in the macula, with slowly progressive loss of central vision. Wet or neovascular AMD is characterized by subretinal hemorrhage, fibrosis and fluid secondary to the formation of CNV, and more rapid and pronounced loss of vision. While less common than dry AMD, neovascular AMD accounts for 80% of the severe vision loss due to AMD. Choroidal neovasculature in exudative (wet) AMD is responsible for the majority of severe vision loss (Freund et al. (1993) Am. J. Ophthalmol. 115(6):786-91). Approximately 200,000 cases of neovascular AMD are diagnosed yearly in the United States alone.
Currently, treatment of the dry form of AMD includes administration of antioxidant vitamins and/or zinc. Treatment of the wet form of AMD, however, has proved to be more difficult. Currently, there are a limited number of methods that have been approved in the United States of America for treating the wet form of AMD. These include laser photocoagulation, PDT using a benzoporphyrin derivative photosensitizer, and intravitreal injection of drugs such as pegaptanib (Macugen®) or ranibizumab (Lucentis®). Laser photocoagulation was until recently the only well-established and widely accepted treatment for CNV. However, it is beneficial only for a small subset of patients, has a high rate of CNV persistence and recurrence and results in iatrogenic, collateral damage to the overlying retina. During laser photocoagulation, thermal laser light is used to heat and photocoagulate the neovasculature of the choroid. A problem associated with this approach is that the laser light must pass through the photoreceptor cells of the retina in order to photocoagulate the blood vessels in the underlying choroid. As a result, this treatment destroys the photoreceptor cells of the retina creating blind spots with associated vision loss.
Another therapeutic modality that can attack CNV without significant collateral damage to the adjacent retina is PDT. Photodynamic therapy utilizes an intravascular photosensitizer that causes vessel occlusion by a non-thermal photochemical reaction (Miller et al. (1999) Arch. Ophthalmol. 117(9):1161-73; Zacks et al. (2002) Invest. Ophthalmol. Vis. Sci. 43(7): 2384-91). During PDT, a benzoporphyrin derivative photosensitizer is administered to the individual to be treated. Once the photosensitizer accumulates in the CNV, non-thermal light from a laser is applied to the region to be treated, which activates the photosensitizer in that region. The activated photosensitizer generates free radicals that damage the vasculature in the vicinity of the photosensitizer (see, U.S. Pat. Nos. 5,798,349 and 6,225,303). This approach is more selective than laser photocoagulation and is less likely to result in blind spots. Under certain circumstances, this treatment has been found to restore vision in patients afflicted with the disorder (see, U.S. Pat. Nos. 5,756,541 and 5,910,510).
During clinical studies, it has been found that recurrence of leakage appears in at least a portion of the CNV by one to three months post-treatment. Increasing photosensitizer or light doses do not appear to prevent this recurrence, and can even lead to undesired non-selective damage to retinal vessels (Miller et al. (1999) Archives of Ophthalmology 117: 1161-1173). Another avenue of investigation is to repeat the PDT procedure over prolonged periods of time. The necessity for repeated PDT treatments can nevertheless be expected to lead to cumulative damage to the retinal pigment epithelium (“RPE”) and choriocapillaris, which may lead to progressive treatment-related vision loss. In addition, PDT can cause transient visual disturbances, injection-site adverse effects, transient photosensitivity reactions, infusion-related back pain, and vision loss. Photodynamic therapy represents a standard treatment for CNV, with variable effectiveness.
Therefore, there is still a need for improved methods for treating AMD characterized by unwanted CNV that increase the efficacy and selectivity of treatment, and which reduce or delay a recurrence of the disorder. There also is a need to improve neuroprotection in the retina overlying the CNV.